Disclosure: Dr. Swamy discusses metformin, which is approved for type 2 diabetes in children and used off-label to treat PCOS in adolescents. Dr. Swamy also discusses spironolactone, which is not FDA-approved for pediatric use. She has no industry relationships to disclose.

CME credit

Polycystic ovarian syndrome (PCOS) is among the most frequent causes of infertility in adult women. PCOS is also the most common cause of menstrual dysfunction and hyperandrogenism in adolescents.[1] It is challenging, yet important, for pediatricians to identify and treat this condition when it presents in childhood and adolescence. Early identification and treatment of PCOS will help prevent long-term consequences, which in addition to infertility, include type 2 diabetes, endometrial hyperplasia and increased risk of carcinoma. This article highlights the differences between adolescents and adult females presenting with PCOS and provides an overview of the diagnostic criteria, pathophysiology, clinical features, differential diagnosis, long-term effects, evaluation, and treatment.

It is estimated that 5%-10% of reproductive age women have PCOS, and this includes adolescents, although accurate data on the prevalence and incidence in this population is unavailable. This is due to the variable nature of this disorder, and the fact that PCOS is often undetected until later in adulthood due to diagnostic challenges.

PCOS manifests with anovulatory symptoms. As adolescents generally have anovulatory and abnormal cycles shortly after menarche, it is difficult to assess anovulatory symptoms in this population. Also, adolescents are often embarrassed to discuss symptoms of hyperandrogenism, and may resort to cosmetic treatments so that the physician is unaware of the extent of hyperandrogenism.

Pathophysiology

The exact cause of PCOS is unknown, however the main abnormality is excessive ovarian androgen production. Insulin and luteinizing hormone (LH) both play a role in this hyperandrogenemia. Increased frequency and amplitude of LH pulses stimulate theca cells in the ovaries to secrete androgens.

Furthermore, insulin resistance is commonly seen in both obese and lean women with PCOS. Insulin resistance results in increased insulin production as a compensatory mechanism. Insulin directly stimulates an increase in LH production, ovarian androgen production, as well as androgen production at the level of the adrenal glands. Insulin also decreases levels of sex hormone binding globulin (SHBG), thereby increasing levels of free androgen. Finally, insulin binds to IGF-1 receptors on the ovary, which increases androgen production as well.

It is well documented that these phenomena occur in adolescence; however, they may begin as early as fetal life. PCOS has been linked to a history of very low birth weight with rapid catch up growth. PCOS is also seen more commonly in girls with a history of premature pubarche.

Diagnostic criteria

The official diagnostic criteria, revised in 2003 at the Rotterdam consensus meeting, and applicable to adult females, include 2 of the following features:

Oligo/Anovulation

Hyperandrogenism – either biochemical or clinical evidence, although it is recommended that laboratory confirmation is established

Polycystic ovaries seen on trans-vaginal ultrasound in adults

It is clear today that the syndrome begins in childhood and adolescence, however, there are no specific criteria in this age group, and the diagnosis is more challenging to make for myriad reasons:

In healthy adolescents, about one-half of menstrual cycles remain anovulatory for 1 to 2 years after menarche.

Adolescents generally have increased terminal hair growth and acne and this transient hyperandrogenism is a normal characteristic of puberty.

Multiple follicular development of ovaries is a normal variant seen in adolescents.

Trans-vaginal ultrasound is not feasible in a non-sexually active adolescent; and therefore, abdominal ultrasounds are recommended, and may result in decreased sensitivity.

Screening

PCOS is an extremely variable entity, and adolescents may present with many or just 1 of the features. The diagnosis should be considered in any adolescent female presenting with:

Mild hirsutism or obesity with any other feature of PCOS (eg, menstrual dysfunction)

Menstrual irregularity which continues for over 2 years after menarche or severe dysfunctional uterine bleeding

Intractable obesity, irrespective of degree of hirsutism or menstrual dysfunction[2]

One must also have a high index of suspicion in children with the aforementioned findings, who have a personal history of premature pubarche, which is now known to be a precursor of PCOS, or a strong family history of metabolic syndrome and/or obesity.

Clinical features

Hirsutism is a key component of PCOS and is defined as excessive terminal hair growth in androgen-dependent areas. It should be distinguished from hypertrichosis, which is generalized hair growth in a non-sexual distribution. Hirsutism is insidious in onset in PCOS. Rapid onset of hirsutism would be concerning for an adrenal or ovarian tumor. The Ferriman-Gallway scoring system is a useful method of quantifying hirsutism. In this system, a score (ranging from 0 for no growth to 4 for extensive growth of terminal hair) is assigned to the following body areas:

Upper lip

Chin

Chest

Upper back

Lower back

Upper abdomen

Lower abdomen

Upper arms

Thighs

Additional areas were included in 2011; however, the above 9 are most commonly used. Generally, a score of over 7 qualifies a woman as hirsute, and scores help standardize our definitions of mild, moderate and severe hirsutism, with higher scores being consistent with moderate and severe levels of hirsutism.

It is important to note that women may present with hirsutism equivalents as well. These include acne, alopecia, seborrhea, hidradenitis suppurativa, and hyperhidrosis. About two-thirds of adolescents with PCOS have clinical evidence of hirsutism or hirsutism equivalents.[3]

Anovulatory symptoms are also seen in about two-thirds of adolescents with PCOS;[3] however, in adolescents, this may be a normal component of puberty. If these problems persist and extend for 2 years after menarche, PCOS should be considered, since it is present in up to 70% of such cases.[4]

Adolescents with PCOS may present with the following:

Primary amenorrhea: lack of menarche by age 15

Secondary amenorrhea: over 90 days without a menstrual cycle, after initiation of menses

Oligomenorrhea: missing over 4 menstrual cycles per year, orfewer than 8 periods per year

Dysfunctional uterine bleeding: frequent or heavy menses

Since menstrual cycles often are anovulatory in the first 1-2 years post menarche, normal cyclicity does not indicate that cycles are ovulatory.

Adolescents with irregular menses have higher plasma androgen levels than those who have regular cycles.[5] Hyperandrogenemia of adolescence generally continues into adulthood,[6] however the condition may not manifest until up to 3 years after menarche.

Polycystic ovaries are the result of follicular arrest in PCOS. Many small follicles develop, but not to the pre-ovulatory size, hence resulting in failure to ovulate. Per an international consensus,[7] a polycystic ovary is one in which 12 or more follicles measuring 2-9 mm in diameter or increased ovarian volume (>10 cm3) are present, as defined by transvaginal ultrasound.

A polycystic ovary is found in the majority of adolescents with PCOS; however this may not occur until years after menarche and may also be present in adolescents without PCOS as a normal pubertal variant. Therefore, abdominal-pelvic ultrasounds are performed in adolescents to exclude other diagnoses, and not necessarily to confirm PCOS.

Obesity and insulin resistance are common components of PCOS. Insulin resistance is frequently evident even in non-obese adolescents. One study reports that 27% of adolescents with PCOS are obese,[8] and the majority are either overweight or obese.[9]

In general, these adolescents have significant abdominal fat known as an android distribution, even if they are not obese. They may also have signs of insulin resistance, such as acanthosis nigricans. In fact, adolescents with PCOS have decreased insulin sensitivity compared with BMI (body mass index)-matched controls.[10]

Long-term effects of PCOS

While type 2 diabetes risk factors such as insulin resistance and glucose intolerance are often seen in patients with PCOS, PCOS itself confers a significant risk, up to 10-fold versus the normal population, for development of type 2 diabetes.[11] It is also associated with an increased risk for sleep apnea, which is independent of the BMI.

In addition to metabolic abnormalities, if untreated, the chronic anovulation of PCOS will result in endometrial hyperplasia and increased risk of endometrial carcinoma. Chronic anovulation resulting in dysfunctional uterine bleeding also may cause anemia. Finally, as noted previously, PCOS is a common cause of infertility.

Differential diagnosis

PCOS accounts for the vast majority of hyperandrogenemia in adolescence. Other conditions share common features and need to be considered in the differential diagnosis. The non-classic form of congenital adrenal hyperplasia (CAH) may also present with androgen excess, menstrual irregularities and premature pubarche, and is not associated with ambiguous genitalia, like the classic form. Non-classic CAH is the second most common cause of androgen excess in this age group.

Other adrenal disorders resulting in over-production of steroids, such as Cushing syndrome, must also be considered. In this condition, the children also have central obesity, along with hypertension, moon faces, dorsal fat pad, striae, muscle weakness, and growth failure.

Hyperprolactinemia affects adrenal androgen production and metabolism, resulting in hirsutism, amenorrhea, and possibly galactorrhea. Drugs including anabolic steroids and valproic acid may cause virilization. Virilizing tumors may also cause hyperandrogenism, but are generally rapid in onset and progression.

Laboratory and imaging evaluation

Given the heterogeneous nature of PCOS, the evaluation and treatment also varies among endocrinologists. The laboratory samples must be drawn early in the morning, at peak time of androgen production, about 8 am. They should also be processed by a trusted laboratory with reliable assays, especially for measurement of free testosterone. In menstruating adolescents, it is best to draw samples in the early follicular phase of their cycle, days 4-10. Table 1 provides a comprehensive list of recommended blood, urine and imaging tests, which should be tailored to each patient and her presentation.

Treatment

The treatment of PCOS is as variable as its presentation and characteristics. Some components of therapy are standard, and others need to be modified to suit the patient.

Weight loss has been proven effective in reducing the progression from impaired glucose tolerance to frank type 2 diabetes mellitus in the Diabetes Prevention Program study.[12] In fact, intensive lifestyle modifications were more effective than metformin alone for prevention.

Similarly, weight loss of at least 5% has significant beneficial effects in women with PCOS, including improvement in hirsutism, acne, and return of ovulation and normal menstrual cycles.[13-14] These studies were performed in adult women, and there are no such comparable studies in adolescents. They are also generally limited in duration, and it is well known that the overwhelming majority of weight loss efforts are transient. Participants generally regain the weight after discontinuation of lifestyle intervention programs.

Metformin, a biguanide, is a well-known oral antidiabetic that reduces hepatic glucose production and improves insulin sensitivity, which thereby results in reduced androgen and LH levels. It is approved by the Food and Drug Administration for children with type 2 diabetes aged 10 years and older, but not specifically for PCOS. Its use in adolescents with PCOS remainsa bit controversial, given the lack of long-term data. A number of studies have demonstrated its efficacy in adolescents with PCOS, but they were short-term studies of 3-6 months in duration and had a limited number of participants.[15-18]

However, the majority of pediatric endocrinologists prescribe metformin in obese adolescents with PCOS and about one-third advocate the use of metformin in all adolescents with PCOS. The American Society for Reproductive Medicine supports the use of metformin in adolescents with PCOS with abnormal glucose tolerance during oral glucose tolerance testing (OGTT). The recommended starting dose is 500 mg daily with gradual increases. Doses of 1500 mg or more daily have demonstrated a positive clinical outcome. Metformin is relatively well-tolerated in adolescents and carries with it a risk of lactic acidosis, though extremely rare.

Oral contraceptive pills (OCPs) are generally regarded as the first-line therapy for treatment of adolescents with PCOS. OCPs normalize menstrual irregularities and reduce androgen levels. The estrogen component reduces LH levels and increases SHBG. Commonly prescribed OCPs include ethinyl estradiol/norgestimate, ethinyl estradiol/norethindrone, and ethinyl estradiol/drospirenone. These are FDA-approved for children post menarche. Studies in adolescents and adults have shown equivalent efficacy among the various estrogen/progesterone combination therapies. OCPs containing low dose estrogen of 20 ug have also been shown to be effective in lowering androgen levels.

Of the progestin components noted above, drospirenone has both anti-androgenic effect and mineralocorticoid activity, which may reduce some of the bloating and water weight gain seen with use of other OCPs. Ethinyl estradiol/drospirenone has fallen under scrutiny lately due to reports of stroke in persons taking the medication.

As with any OCP, a thorough family history should be obtained and these medications are not recommended in women with a personal or family history of coagulopathies (which includes hypercoagulable states), or women with other risk factors for a clot or stroke (eg, smoking, hyperlipidemia).

OCPs normalize androgen levels within a few weeks, however reduction in terminal hair may not be appreciated for as long as 9 months after initiation of treatment. Once patients begin to ovulate, they need to be counseled regarding preventing unwanted pregnancy.

Anti-androgens include spironolactone, which is not FDA-approved for pediatric use. As these medications have teratogenic potential, they should be used in conjunction with an oral contraceptive, and not as monotherapy. The Endocrine Society’s clinical practice guidelines for treatment of hirsutism are an excellent resource, providing a detailed review of these medications, including evidenced-based support for their use, efficacy, and adverse effects. (See http://www.endo-society.org/guidelines/Current-Clinical-Practice-Guidelines.cfm.)

It is generally recommended that OCPs as first-line therapy be utilized for at least 6 months prior to considering the addition of an anti-androgen. If the adolescent is still complaining of significant hirsutism after a 6-month trial of OCPs, discuss compliance as this may play a role and then consider addition of an anti-androgen. One must also keep in mind that terminal hair growth changes may take over 9 months to manifest; therefore, postponing the addition of these agents until 6-9 months after initiating first-line therapies is recommended.

Spironolactone is the most commonly used anti-androgen in the American adolescent population. OCPs and metformin are comparatively much more widely used, however. Doses of 25 mg BID – 100 mg daily of spironolactone have been proven to be effective in treating hyperandrogenism. A study comparing spironolactone to metformin in adolescents and young adults demonstrated that spironolactone “appears better than metformin in the treatment of hirsutism, menstrual cycle frequency, and hormonal derangements and is associated with fewer adverse events.”[19] In this study, however, spironolactone did not have any beneficial effects on insulin levels. Spironolactone can cause hyperkalemia, and potassium levels should be monitored.

Cosmetic treatments: As many of the above medications require months to produce clinical results, patients may seek cosmetic treatments, such as topical anti-androgens or hair removal. Topical anti-androgens tend to be ineffective.

Conclusion

Although recognizing PCOS in adolescents is inherently challenging, early identification and treatment can help prevent infertility, type 2 diabetes, and other serious consequences of this disorder. Pediatricians should evaluate for PCOS in any girl presenting with menstrual irregularity over 2 years after menarche, hirsutism, refractory acne, or obesity, especially when patients with any of these features had premature pubarche and a family history of metabolic syndrome or obesity.

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